Variability In Dose Requirements Research Articles

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Variant-based heritability assessment of dexmedetomidine and fentanyl clearance in pediatric patients.

Despite complex pathways of drug disposition, clinical pharmacogenetic predictors currently rely on only a few high effect variants. Quantification of the polygenic contribution to variability in drug disposition is necessary to prioritize target drugs for pharmacogenomic approaches and guide analytic methods. Dexmedetomidine and fentanyl, often used in postoperative care of pediatric patients, have high rates of inter-individual variability in dosing requirements. Analyzing previously generated population pharmacokinetic parameters, we used Bayesian hierarchical mixed modeling to measure narrow-sense (additive) heritability ( ) of dexmedetomidine and fentanyl clearance in children and identify relative contributions of small, moderate, and large effect-size variants to . We used genome-wide association studies (GWAS) to identify variants contributing to variation in dexmedetomidine and fentanyl clearance, followed by functional analyses to identify associated pathways. For dexmedetomidine, median clearance was 33.0 L/h (interquartile range [IQR] 23.8-47.9 L/h) and was estimated to be 0.35 (90% credible interval 0.00-0.90), with 45% of attributed to large-, 32% to moderate-, and 23% to small-effect variants. The fentanyl cohort had median clearance of 8.2 L/h (IQR 4.7-16.7 L/h), with estimated of 0.30 (90% credible interval 0.00-0.84). Large-effect variants accounted for 30% of , whereas moderate- and small-effect variants accounted for 37% and 33%, respectively. As expected, given small sample sizes, no individual variants or pathways were significantly associated with dexmedetomidine or fentanyl clearance by GWAS. We conclude that clearance of both drugs is highly polygenic, motivating the future use of polygenic risk scores to guide appropriate dosing of dexmedetomidine and fentanyl.

Ethnic Diversity and Warfarin Pharmacogenomics.

Warfarin has remained the most commonly prescribed vitamin K oral anticoagulant worldwide since its approval in 1954. Dosing challenges including having a narrow therapeutic window and a wide interpatient variability in dosing requirements have contributed to making it the most studied drug in terms of genotype-phenotype relationships. However, most of these studies have been conducted in Whites or Asians which means the current pharmacogenomics evidence-base does not reflect ethnic diversity. Due to differences in minor allele frequencies of key genetic variants, studies conducted in Whites/Asians may not be applicable to underrepresented populations such as Blacks, Hispanics/Latinos, American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders. This may exacerbate health inequalities when Whites/Asians have better anticoagulation profiles due to the existence of validated pharmacogenomic dosing algorithms which fail to perform similarly in the underrepresented populations. To examine the extent to which individual races/ethnicities are represented in the existing body of pharmacogenomic evidence, we review evidence pertaining to published pharmacogenomic dosing algorithms, including clinical utility studies, cost-effectiveness studies and clinical implementation guidelines that have been published in the warfarin field.

Psychoactive Substances and Drugs-Medicament and Narcotic

Toxicological analysis is a complex set of tasks aiming to estimate how much time has elapsed since a drug was last consumed or to inform about its chronic consumption. It is also worth paying attention to the fact of using psychoactive substances induce euphoria or increase physical energy. The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics could be used to adapt pain medication based on an individual’s genetic background. Many potential genetic markers related to xenobiotics metabolism have been described. Such predictors are especially of value for neonates and young children, in which case the assessment of efficacy is complicated by imprecise/poor communication. The knowledge of opioids metabolism is essential also for older patients and those with comorbidities, who receive multiple medications and may have impaired renal and hepatic function.

Differences in Predicted Warfarin Dosing Requirements Between Hmong and East Asians Using Genotype-Based Dosing Algorithms.

Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian subpopulation numbering over 278,000 in the United States whose participation in genetics-based research is virtually nonexistent. The translational significance of early reports of warfarin pharmacogene differences in Hmong has not been evaluated. (i) To validate previously identified allele frequency differences relevant to warfarin dosing in Hmong versus East Asians and (ii) to compare predicted warfarin sensitivity and maintenance doses between a Hmong population and an East Asian cohort. DNA collected from two independent cohorts (n=236 and n=198) of Hmong adults were genotyped for CYP2C9 (*2, *3), VKORC1 (G-1639A), and CYP4F2 (*3). Allele frequencies between the combined Hmong cohort (n=433) and East Asians (n=1165) from the 2009 International Warfarin Pharmacogenetics Consortium (IWPC) study were compared using a χ2 test. Percentages of Hmong and East Asian participants predicted to be very sensitive to warfarin were compared using a χ2 test, and the predicted mean warfarin maintenance dose was compared with a t test. The allele frequencies of CYP2C9*3 in the combined Hmong cohort and CYP4F2*3 in the VIP-Hmong cohort are significantly different from those in East Asians (18.9% vs 3.0%, p<0.001 and 9.8% vs 22.1%, p<0.001, respectively). Comparing the combined Hmong cohort to the East Asian cohort, the percentage of participants predicted to be very sensitive to warfarin was significantly higher (28% vs 5%, p<0.01) and the mean predicted warfarin maintenance dose was significantly lower (19.8 vs 21.3mg/week, p<0.001), respectively. The unique allele frequencies related to warfarin when combined with nongenetic factors observed in the Hmong translate into clinically relevant differences in predicted maintenance dose requirements for Hmong versus East Asians.

Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy.

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health economics, and drug regulations.

Dosing algorithm for Tacrolimus in Tunisian Kidney transplant patients: Effect of CYP 3A4*1B and CYP3A4*22 polymorphisms

Prescribing appropriate Tacrolimus (Tac) dosing is still a challenge for clinicians due to the interindividual variability in dose requirement and the narrow therapeutic index. Our objective is to identify potential factors that affects Tac exposure in Tunisian Kidney patients and to develop and validate a Tac dose requirement algorithm including genetic and nongenetic variables.A cross-sectional study was performed. To assess the implication of each covariate on Tac exposure, we classified the patients according to quartiles of exposure index (trough Tac concentration/Dose: C0/D). The total population was divided into the building (75%) and validation (25%) groups. Multiple linear regression was applied to determine the algorithm of Tac dose including the patient's genetic and nongenetic variables.A total of 685 samples issued from 102 kidney transplant patients were included in the study. The post-transplant time (PT), ATG therapy, CYP3A4, and CYP3A5 polymorphisms were significantly associated with trough Tac C0/D. However, the age, sex, body weight, and induction by basiliximab did not show any effect on C0/D. Predicted Tac dose was calculated as follows:Tac Dose = − 2,725 - (10−3 * PT day) + (0,09*weight) + (1,40*ATG) + (2,09* CYP3A4*1B allele) + (0,88*gender) + (0,05*Age) + (1,10*CYP3A4*22 allele) + (2,30* target ranges).Our study designed the first algorithm that predicts the Tac dose requirement in Tunisian Kidney transplant patients including genetic and non-genetic factors.The application of such an algorithm should reduce the number of patients with Tac trough concentration outside the target range and could minimize the time to reach a therapeutic C0.

Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms on theVariability on Warfarin Dosage Requirements and Susceptibility to CVD in the Jordanian Population.

The purpose of this study was to investigate the effects of the SH2B3, MTHFD1L, GGCX, and ITGB3 gene variants on the efficacy of warfarin treatment and its effects on the risk of cardiovascular disorders in Jordanian patients. The selected genes and their polymorphisms are involved in many Genome-Wide Association Study (GWAS) associated with cardiovascular disease and the variability of warfarin therapy. The current study conducted a genetic association and pharmacogenetics study in (212) Jordanian cardiovascular patients treated with warfarin and (213) healthy controls. DNA extraction and the Mass ARRAY™ system were used to genotype ten selected polymorphisms within four genes (SH2B3, MTHFD1L, GGCX, and ITGB3). This study confirmed a genetic association of MTHFD1L rs6922269 Single Nucleotide Polymorphism (SNP) with warfarin sensitivity during the initial and stabilization phases of treatment. Moreover, this SNP showed significant differences in the initial and maintenance doses of warfarin. This study also found an association between the genetic haplotypes (AGC and GAT) within the SH2B3 gene and responsiveness to warfarin. However, possession of an MTHFD1L rs491552 variant allele was found to affect the outcome measure of the international normalized ratio (INR) during the stabilization phase of warfarin treatment. In contrast, there was no association between all selected SNPs and susceptibility to cardiovascular disorders. This study extends the current understanding of the high variability of the warfarin response, including variability in dose requirements and susceptibility to cardiovascular disease in the Jordanian-Arab population. Other studies on a larger sample and in different ethnic groups could help to better understand the pharmacogenetics of warfarin and its application in personalized medicine.

Pharmacogenomics of vitamin K antagonists

There is an important interindividual variability in dose requirement for coumarinic anticoagulants, which could be explained by genetic and non-genetic factors. Among hereditary factors, there are gene polymorphisms that code the therapeutic target and the main enzyme responsible for their metabolism. However, there are other candidate genes that could modulate dose requirements. The is a paucity of pharmacogenomic platforms to determine dose requirements of coumarinics in the Chilean population. Therefore, algorithms considering different variables to adjust individual dosages are required. Herein, we analyze the available evidence about factors that can modify the effects of vitamin K antagonists and that should be incorporated to dosing algorithms.

Comparing outcomes and costs among warfarin-sensitive patients versus warfarin-insensitive patients using The Right Drug, Right Dose, Right Time: Using genomic data to individualize treatment (RIGHT) 10K warfarin cohort.

Oral anticoagulant (OAC) therapy has been the main treatment approach for stroke prevention for decades. Warfarin is the most widely prescribed OAC in the United States, but is difficult to manage due to variability in dose requirements across individuals. Pharmacogenomics may mitigate risk concerns related to warfarin use by fostering the opportunity to facilitate individualized medicine approaches to warfarin treatment (e.g., genome-guided dosing). While various economic evaluations exist examining the cost-effectiveness of pharmacogenomics testing for warfarin, few observational studies exist to support these studies, with even fewer using genotype as the main exposure of interest. We examined a cohort of individuals initiating warfarin therapy between 2004 and 2017 and examined bleeding and cost outcomes for the year following initiation using Mayo Clinic’s billing and administrative data, as well the Mayo Clinic Rochester Cost Data Warehouse. Analyses included descriptive summaries, comparison of characteristics across exposure groups, reporting of crude outcomes, and multivariate analyses. We included N = 1,143 patients for analyses. Just over a third of our study population (34.9%) carried a warfarin-sensitive phenotype. Sensitive individuals differed in their baseline characteristics by being of older age and having a higher number of comorbid conditions; myocardial infarction, diabetes, and cancer in particular. The occurrence of bleeding events was not significantly different across exposure groups. No significant differences across exposure groups existed in either the likelihood of incurring all-cause healthcare costs or in the magnitude of those costs. Warfarin-sensitive individuals were no more likely to utilize cardiovascular-related healthcare services; however, they had lower total and inpatient cardiovascular-related costs compared to warfarin-insensitive patients. No significant differences existed in any other categories of costs. We found limited evidence that warfarin-sensitive individuals have different healthcare spending than warfarin-insensitive individuals. Additional real-world studies are needed to support the traditional economic evaluations currently existing in the literature.

Sex Bias and Genotype Influence on Opioid Safety Profile in Chronic Low Back Pain.

The use of opioids to relieve pain is a challenge because of the high variability in dose requirements and tolerance profiles. Among potential modulators are the individual's genetic background and being female. Our aim was to evaluate sex bias and genotype-related influence on opioid titration safety, in chronic low back pain (CLBP), the most frequent chronic noncancer pain. A 3-year prospective study was developed in opioid-naive CLBP patients. Data were self-reported by patients (pain [Visual Analogy Scale], adverse events [AEs], and health care resource utilization) and physicians (analgesic prescription, morphine equivalent daily dose, and suspected adverse drug reactions [ADRs]). Outcomes were analyzed as patients with AEs (case) or without (control) together with patients' sex and genotype. Gene variants in OPRM1 (rs1799971), COMT (rs4680), ABCB1 (rs1045642), UGT2B7 (rs12233719 and rs7438135), KCNJ6 (rs2070995 and rs6517442), and CYP3A5*3 (rs776746) were assessed. The hospital ethics committee approved the study, and statistical analyses were performed with R, v.3.2.4. A total of 179 patients were included (64% female, mean pain intensity 73±16 mm), and 90% of them presented at least 1 AE (median of 3 (1 to 6) AEs/patient) with a rate of 5 AEs: 1 ADR without differences due to sex. However, there is a significant delay in referral of female patients (a mean of 6 years) to the Pain Unit, being significantly 3 to 5 times more likely to present sleep or psychiatric disorders. Meanwhile male individuals showed more sexual and reproductive system disorders. Genotypes influenced skin (COMT, G472A-GG) and gastrointestinal (ABCB1, C3435T-CC) related problems. Sex bias affects female patients resulting in a CLBP diagnostic delay and a different analgesic safety profile. Moreover, the individual's genetic background might be useful to predict certain AEs in opioid-naive patients under an opioid titration procedure. Addressing sex in necessary to resolve inequalities in health care access.

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.

Association between VKORC1 gene polymorphism and warfarin dose requirement and frequency of VKORC1 gene polymorphism in patients from Kerman province

Warfarin is an anticoagulant prescribed in the treatment and prevention of thrombosis. Variation in dose requirements is different for everyone, and genetic factors have an effect on dose variation. Polymorphism of vitamin K epoxide reductase complex 1 (VKORC1) gene is identified as the main genetic factor involved in warfarin dosage requirement variations. This study aims to determine the frequency of VKORC1 polymorphism in patients using warfarin from Kerman city and investigated association between VKORC1 gene polymorphism and patient characteristics with warfarin dose requirement. A total of 112 patients taking warfarin with stable dose requirements enrolled in the study. DNA samples from these patients were genotyped for VKORC1 gene polymorphism by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP) and examined associations between demographic characteristics (e.g. age, sex, smoking, etc.) and genetic factors with maintenance dose of warfarin. The most common genotype was VKORC1 GA (48.2%). genotype frequency subjects carried VKORC1 GG and AA were 39.3% and 12.5%, respectively. In addition, a significant relationship was found between VKORC1-1639G>A and the daily dose of warfarin (P = 0.011, R2 = 0.080). The frequencies of the VKORC1-1639 A alleles were significantly lower than VKORC1-1639 G alleles and required fewer warfarin dose.

Algorithm for predicting low maintenance doses of warfarin using age and polymorphisms in genes CYP2C9 and VKORC1 in Brazilian subjects.

Warfarin exhibits a wide variation in dose requirements. We sought to evaluate the association of polymorphisms CYP2C9*2 (rs1799853), CYP2C9*3 (rs1075910), and VKORC1-G1639A (rs9923231) and nongenetic factors with maintenance doses of warfarin <17.5 mg/week and to create an algorithm to predict drug sensitivity. This is a retrospective cohort study including 312 patients assisted at an anticoagulation clinic in Brazil. The mean age of participants was 60.4 ± 13.5 years and 59.9% were female. The logistic regression model included: age [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06], genotype VKORC1 AA (OR 31.61, 95%CI 11.20-100.15) and genotype CYP2C9 2/2, 2/3 or 3/3 (OR 16.48, 95%CI 3.37-81.79). The creation of our algorithm involved warfarin-experienced patients on stable doses, identifying factors associated with drug sensitivity. The validation of this algorithm allows its use in future populations to determine the initial dose distinguishing patients with dose requirements <17.5 mg and reducing time to achieve stable doses.

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study

Background The large variability in dose requirement of vitaminK antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient;however,this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochromeP450 (CYP)2C9, vitaminK epoxide reductase complex subunit1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥3weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Use of Individual Pharmacokinetics to Improve Time to Therapeutic Vancomycin Trough in Pediatric Oncology Patients.

Optimization of vancomycin dosing is difficult in children, given rapid drug clearance and patient heterogeneity. We sought to evaluate the impact of dosing using individual pharmacokinetic parameters on time to goal trough concentration in pediatric oncology patients. A retrospective review was conducted to assess vancomycin dosing in the pediatric oncology unit at Loma Linda University Children's Hospital between January 2013 and August 2013 (standard dosing group [SDG]). These patients were compared to those in a prospective arm that used pharmacokinetic dosing (pharmacokinetic dosing group [PKG]) between March 2014 and May 2015. Outcomes included percent of patients reaching a target trough by the specified time points, number of dose adjustments, number of serum concentrations drawn, and number of patients with supratherapeutic troughs. Of 35 patients meeting inclusion criteria for the SDG, 2 (5.7%) reached goal trough concentration by 48 hours, compared with 14 of 16 patients (87%) in the PKG (p = 0.0001). Significantly more patients reached their goal trough at each time point in the PKG. There was no difference in number of dose adjustments, but significantly more concentrations were drawn on average in the PKG (mean, 4.6 versus 3.1, p = 0.02). In the SDG and PKG, respectively, 1 patient and 3 patients had supratherapeutic trough concentrations (p = 0.09). Dosing using individual pharmacokinetic parameters led to a significant reduction in time to attain the desired vancomycin trough concentration in our pediatric oncology patients. Given the wide variation in dose requirements in this and other studies, application of patient-specific pharmacokinetics is essential to optimize vancomycin dosing in pediatric patients.

Targeted and global pharmacometabolomics in everolimus-based immunosuppression: association of co-medication and lysophosphatidylcholines with dose requirement.

The immunosuppressive therapy with everolimus (ERL) after heart transplantation is characterized by a narrow therapeutic window and a substantial variability in dose requirement. Factors explaining this variability are largely unknown. Our aim was to evaluate factors affecting ERL metabolism and to identify novel metabolites associated with the individual ERL dose requirement to elucidate mechanisms underlying ERL dose response variability. We used liquid chromatography coupled with mass spectrometry for quantification of ERL metabolites in 41 heart transplant patients and evaluated the effect of clinical and genetic factors on ERL pharmacokinetics. Non-targeted plasma metabolic profiling by ultra-performance liquid chromatography and high resolution quadrupole-time-of-flight mass spectrometry was used to identify novel metabolites associated with ERL dose requirement. The determination of ERL metabolites revealed differences in metabolite patterns that were independent from clinical or genetic factors. Whereas higher ERL dose requirement was associated with co-administration of sodium-mycophenolic acid and the CYP3A5 expressor genotype, lower dose was required for patients receiving vitamin K antagonists. Global metabolic profiling revealed several novel metabolites associated with ERL dose requirement. One of them was identified as lysophosphatidylcholine (lysoPC) (16:0/0:0). Subsequent targeted analysis revealed that high levels of several lysoPCs were significantly associated with higher ERL dose requirement. For the first time, this study describes distinct ERL metabolite patterns in heart transplant patients and detected potentially new drug-drug interactions. The global metabolic profiling facilitated the discovery of novel metabolites associated with ERL dose requirement that might represent new clinically valuable biomarkers to guide ERL therapy.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice.

The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

Predictors of warfarin dose requirements in South African patients attending an anticoagulation clinic

Warfarin is the most common oral anticoagulant for the treatment and prevention of thromboembolic disease. However, it has a wide interpatient variability in dose requirements due to various genetic and clinical factors. This study investigated the effect of clinical and genetic factors on the variability of warfarin dose requirements in 147 South African patients (81 white and 66 black). The study was performed at a University Hospital Anticoagulation Clinic managed by nursing sisters at the Charlotte Maxeke Johannesburg Academic Hospital. The most common indication for anticoagulation was atrial fibrillation (n=55, 37.4%). The mean warfarin dose was significantly higher in black patients as compared to white patients (5.4±2.9mg/day and 3.8±2.1mg/day, respectively; P<0.001). Older age was significantly associated with a lower maintenance warfarin dose (P<0.001). Drugs which decreased the international normalized ratio (INR) were significantly associated with a higher maintenance warfarin dose of 6.4±3.4mg/day (P<0.034). In contrast, there was no significant difference in warfarin dosage requirements in the presence of CYP2C9 and VKORC1 variant alleles (P>0.05). Patients, however, homozygous for CYP2C9 *1,*3, and VKORC1 required less than 5mg/day of warfarin to maintain the INR within the therapeutic range. In conclusion, this study indicates that clinical characteristics including; age, ethnic group, and drugs which decrease the INR might help to predict better dose requirements in this population group and thereby reduce the risk of bleeding and thrombotic complications.

Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population.

BackgroundWarfarin is a widely prescribed anticoagulant with narrow therapeutic window for thromboembolic events. Warfarin displays large individual variability in dose requirements. The purpose of this study is to assess the contribution of patient-specific and genetic risk factors to dose requirements of patients on either high or low warfarin maintenance dose in Ghana. Blood samples were collected from 141 (62 males, 79 females) Ghanaian patients on stable warfarin dose to determine their INR. Influence of patient specific factors and gene variations within VKORC1, CYP2C9 and CYP4F2 were determined in patients on either high or low warfarin maintenance dose.ResultsOne hundred and forty-one patients took part in the study with 79 (56%) participants being Female. The median age of the study participants was 48 years [IQR: 34–58]. The median duration for patients to be on warfarin therapy was 24 months [IQR: 10–72]. Majority of the study participants (80.9%, n = 114) did not have any side effects to warfarin. CYP2C9*2 and CYP2C9*3 variant alleles were not detected. VKORC1 variant allele was observed at 6% and CYP4F2 variant allele was observed at 41%. Duration of patients on warfarin therapy was marginally associated with high warfarin dose (adjusted OR = 1.01 [95% CI 1.00–1.02], p = 0.033) while the odds of heterozygous individuals (G/A) for VKORC1 gene to have high warfarin dose compared to persons with homozygous (G/G) (adjusted OR = 0.06 [95% CI 0.01–0.63], p = 0.019). Age, gender, diagnosis, presence of side effects and other medications were not associated with warfarin dose (p = 0.05).ConclusionThis study provides data on VKORC1 and CYP4F2 variants among an indigenous African population. Duration of patients on warfarin therapy was marginally associated with high warfarin dose. CYP2C9*2 and *3 variants were not detected and may not be the most important genetic factor for warfarin maintenance dose among Ghanaians.